UA86816C2 - Chewable, suckable and swallowable tablet containing a calcium-containing compound as an active substance - Google Patents

Abstract

The present invention relates to a nutriceutical and/or pharmaceutical composition for oral use containing a calcium-containing compound. The composition is in the form of tablets that are designed so that they have an acceptable taste and moothfeel, whereby the tablets are chewable or suckable, and at the same time the tablets fulfil the requirements with respect to technical properties in order to ensure that the tablets can be dispensed by means of a dose-dispensing machine. In a preferred embodiment, the tablet comprises calcium carbonate and sorbitol with a mean particle size of 38 or 110 microns. In another embodiment, the tablets comprise calcium carbonate and Vitamin D as active ingredients.

Description

The present invention relates to a nutraceutical and/or pharmaceutical composition for oral use containing a calcium-containing compound. The composition is in the form of a tablet designed to have an acceptable taste and mouth feel, i.e. the tablets are suitable for chewing or sucking, and at the same time the tablets meet the technical properties required to ensure that the tablets can be dispensed by a dispensing machine. distribution of doses.

In today's world, the main main areas of global health care are undergoing significant changes. The future holds further advancement of the drug with an increasing elderly population requiring increased care. To improve compliance (adherence to doctor's prescriptions), for example for the elderly, the packaging of the medicinal product in daily/multi-dose packaging ("split dose") is increasingly carried out, for example in European countries. Usually, the medicine is taken over a period of two weeks and the daily dose pack contains, for example, morning, noon, evening and night packs/packets. Information about the person and the medicine is printed on each package.

Developing tablets that are strong enough to be dispensed through a dispensing machine is a particular challenge in the development of chewable tablets. Of course, chewable tablets do not have sufficient technical properties that are required for a dosing machine (for example, tablets are very fragile, when placed in the equipment that fills the machine, they create dust that makes filling difficult or impossible). Today, there are no products on the market that would contain a calcium-containing compound as a therapeutically and/or prophylactically active substance and would be chewable, that is, provide an acceptable taste and mouthfeel, and at the same time possess sufficient technical properties to allow dispensing by machine for the distribution of doses. Accordingly, patients may not place a daily dose package into a dosing machine if the package includes one or more calcium-containing chewable tablets. The inventors address this problem by providing a tablet that is strong enough to withstand packaging in a dispensing machine, yet one that allows the patient or consumer the freedom to choose whether he/she wants to chew, suck, and/or swallow. tablet, that is, the improved technical properties do not reduce the acceptable taste and sensation in the mouth.

As mentioned above, there is a need for the development of an improved pharmaceutical composition comprising a calcium-containing compound, the composition of which will be suitable for packaging by means of a machine for dispensing doses, and at the same time for chewing. As far as the inventors know from a careful study of the state of the art, such a composition does not exist today, most likely because chewable tablets containing a calcium-containing compound must meet very high requirements regarding organoleptic properties, in particular, taste and mouthfeel. In fact, it has been previously described that the quality of the calcium-containing compound, as well as the method of making the pharmaceutical composition containing the calcium-containing compound, are very important to obtain an acceptable taste and mouthfeel for a chewable tablet (MO 00/28973). The method described in UUO 00/28973 is related to a process in a fluidized bed, by means of which a granulate is obtained for the production of tablets that have suitable organoleptic properties. However, such tablets do not have the necessary mechanical stability to withstand dispensing with a dispensing machine. In addition, the fluidized bed process often leads / to the formation of a granulate with a very high porosity, from 2095 to 3095, which in turn leads to porous tablets, that is, in this context, such tablets may be too large to fit into the cassettes of the machine for distribution of doses. A pharmaceutically acceptable sugar alcohol used in accordance with the invention has an average particle size of at most about 150 µm, such as, for example, at most about 110 µm, at most about 100 µm, at most about 00 µm, at most about 8 µm, at most about 7 µm, at most about bΩm, at most about 5BOμm, at most about 40μm, at most about 20μm or about 1Ωm. In a specific embodiment, the pharmaceutically acceptable sugar alcohol used has an average particle size in the range of about 5 to about 15 Ωm, such as, for example, from about 5 to about 11 Ωm or from about 5 to about 8 Ωm.

Also, to ensure a high level of compliance, even in those situations where a chewable tablet is, for example, swallowed, the inventors aimed to develop a tablet that meets all the requirements for chewable tablets, lozenges and swallowable tablets. In this context, chewable tablets include tablets that can be chewed. Normally, the requirements for chewable tablets are the exact opposite of those for swallowing tablets (for example, chewable tablets must not disintegrate but must "melt" on the tongue, while swallowing tablets are much stronger but must meet disintegration and dissolution requirements active ingredient). In addition, chewable tablets do not normally meet the stability requirement applicable to tablets intended for dispensing by means of a dispensing machine and set by national regulatory authorities. The specified requirement is that the tablets should be stable when stored outside the package, i.e. in open Petri dishes at 25°C and 6095 relative humidity (RH) for 1 month. Known chewable tablets containing a calcium-containing compound turn gray or change color in the process of storage and, in general, cannot meet the above requirements.

The inventors have solved this problem by providing a tablet that contains a calcium-containing compound as an active substance, a tablet that has the properties necessary for dispensing with a dose-dispensing machine, and a tablet that has an acceptable taste and mouthfeel when tested for organoleptic properties by a group of professional, experienced researchers at least with b persons. In this context, a group of professional, experienced testers means testers who have the ability or are trained to have the ability to evaluate the taste and sensation in the mouth of products intended for consumption.

In addition, i) a high dose of calcium carbonate (normally 300-6b0Omg of elemental calcium twice a day, which corresponds to 750-1500 mg of calcium carbonate twice a day), i) natural bad properties of calcium carbonate with a regular particle shape from the point of view of tableting, such as compressibility, which accordingly creates the need for the addition of one or more pharmaceutically acceptable excipients in order to obtain a suitable compressibility: and iii) extremely bad taste or mouthfeel for the calcium salt itself, especially given the chalky feel makes it very difficult in terms of producing a tablet that has a suitable small size that is conventionally small for the patient. Adequate taste masking is another challenge when formulating chewable tablets.

In order to produce a tablet of smaller size that still has an acceptable taste and mouth feel, the inventors have found that the use of pharmaceutically acceptable sugar alcohols as a binding material in the agglomeration process is particularly suitable. To this end, the inventors found that when using a calcium-containing compound with a regular particle shape, which itself has very poor pressing properties, to obtain an acceptable final result, it is important to use a pharmaceutically acceptable sugar alcohol with a particle size (0(m;0.5u less than 150μm , resulting in a tablet with a porosity of less than 2095. In a preferred embodiment, a roller compacted composition containing a calcium-containing compound is used, and it is very important that the sugar alcohol used also has a microstructure, i.e., a structure that allows a certain deformation, for example, during the compaction process, in order to create a sufficient connection between the individual particles of calcium (and sugar alcohol).

Accordingly, the invention relates to a tablet containing a calcium-containing compound suitable for dispensing by means of a dose-dispensing machine, a tablet comprising a calcium-containing compound with a regular particle shape as an active substance and a pharmaceutically acceptable sugar alcohol having a microstructure, the tablet being stable when tested in in open Petri dishes at 25"7C and 6095 relative humidity (RH) for 1 week or more, for 2 weeks or more, for 3 weeks or more, for 4 weeks or more, for 1 month or more, for 2 months or more, or for 3 months or more.

In this context, the term "with a regular particle shape" in connection with a calcium-containing compound is intended to indicate that the individual particles have a rounded or flat surface, similar, for example, to cubic crystals. The regular shape leads to a relatively low specific surface area, which is less than 1.5m2/g.

In this context, the term "microstructure" used in connection with sugar alcohols is intended to indicate that a single crystal of a sugar alcohol is a polycrystal, such as multiple crystals or fibrous crystals, which can be detected by SEM data. The microstructure allows a certain degree of deformation and sufficient distribution in the tablet during the roller compaction process in order to achieve sufficient bonding between individual particles of calcium (and sugar alcohol).

The present invention is based on the discovery that the use of sugar alcohols of specific quality categories in tablets results in tablets which are stable when stored in open Petri dishes as described above.

In addition, in the manufacture of chewable tablets, they should not be so hard, that is, have an unacceptably high resistance to crushing, in such a way that it will be difficult for the patient to chew. Accordingly, it is important to balance the crush resistance to an acceptable level. The inventors have discovered that it is possible to determine whether a particular sugar alcohol is suitable for use in the production of a free-flowing material in accordance with the invention by conducting two tests of the sugar alcohol, namely i) a SEM photograph showing that the sugar alcohol has a microstructure, or i) an analysis that demonstrates the pressing properties of the sugar alcohol itself. For this purpose, pharmaceutically acceptable sugar alcohol - when pressed into tablets containing 10095 (w/w) of sugar alcohol, using flat punches of 11.29 mm and a maximum pressing force of 25 kKN - has a slope of correlation between resistance to crushing (measured in H) and pressing pressure (measured in N) 7x103 or more, when tested using Zspieipideg Nagapev5

Ashoievziei 4 or 5sPpiieipideg Tariyei ieziei 6O and containing tablets with the longest dimension located orthogonally to the clamps of the apparatus for measuring resistance to crushing.

Moreover, contrary to the prior art in the field of dosage forms, the inventors have found that a sugar alcohol, such as sorbitol, of the standard quality category that is usually recommended, is unsuitable for use. This category has an average particle size of about 30 µm, but this average particle size is too large to allow sufficient distribution of the sorbitol particles around the calcium-containing compound particles, resulting in tablets with unacceptable crush resistance. To obtain good and acceptable results from the point of view of resistance to crushing, the particle size of, for example, sorbitol should be much smaller.

Accordingly, a pharmaceutically acceptable sugar alcohol used in accordance with the invention has an average particle size of at most about 150 µm, such as, for example, at most about 110 µm, at most about 100 µm, at most about 900 µm, at most about 80 µm, at most about 7 µm, at most about bΩm , at most about 5 µm, at most about 40 µm, at most about 20 µm, or at most about 1 µm.

In a particular embodiment, the pharmaceutically acceptable sugar alcohol used has an average particle size in the range of from about 5 to about 15 µm, such as, for example, from about 5 to about 1100 µm or from about 5 to about 8 µm.

Furthermore, the use of, for example, sorbitol with a much smaller particle size would be expected to lead to stability problems, as sorbitol is known to be hygroscopic and a smaller particle size increases the surface area and thus increases the risk of moisture adsorption, e.g. environment. However, as demonstrated in this specification, tablets made using a granulate obtained by roller compaction of a composition containing a calcium-containing compound and, for example, sorbitol with an average particle size of much less than 30 µm, are stable in terms of resistance to crushing, i.e. stability of crushable tablets when stored in open petri dishes at 257°C and 6095 RH changes by at most 5095, such as, for example, at most about 4095, at most about 3095, at most about 2095, at most about 1595, at most about 1095 for a period of time beginning 5 days after storage in open Petri dishes and continuing for the remainder of the storage period of 90 days.

Such improved stability shows that the product obtained as described in this specification is suitable for so-called countries of zone C or 4 (as defined in the ISN CE), that is, countries with relatively high average temperature and relative humidity.

In order to ensure sufficient distribution of the pharmaceutically acceptable sugar alcohol between the individual particles of the calcium-containing compound, for example in a roller compaction process, the inventors have found that a suitable binding agent has an average particle size of at most about 150 µm, e.g. at most about 1100 µm, at most about 100 µm, at most about 900 µm, at most about 8 µm, at most about 70 µm, at most about 100 µm, at most about 500 µm, at most about 40 µm, at most about 20 µm, or, for example, about 1 µm.

In the literature (see Ripaptaseshisa! Thesppoiodu, myoshte 1 (abrienipd iesppoiodu), Misnae! N. Rybipzieip (ed),

ESHPv8 Nopmoa CA, 1987) states that sorbitol has good tableting properties and that premixing with this excipient will increase tablet strength. However, it is also stated that in order to achieve such an effect, the sorbitol must be of the "soluble" category, which is produced by spray drying. The optimal particle size of "soluble" sorbitol is described as such when 60-9095 are in the range of 212-500μm when determined by sieve analysis. The recommended concentration in a tablet is 30-8095. However, in the context of this invention, sorbitol can be used as a binding agent (with sweetening properties) in tablets:

Specifically, two sugar alcohols have been proven to be suitable for use in the roller compaction process, namely sorbitol and isomalt. However, the invention also covers other sugar alcohols that may be suitable in a quality category that meets the above criteria, and it is intended that such sugar alcohols will be suitable for use in accordance with the invention. Below are other sugar alcohols that may satisfy the above criteria.

In a specific embodiment, the sugar alcohol is sorbitol, namely sorbitol having an average particle size in the range of about 25 to 500 microns, for example, about 35 to 45 microns.

In another embodiment, the sugar alcohol is isomalt, namely isomalt having an average particle size in the range of about 20 to 5 µm, for example, from about 25 to 35 µm.

Sugar alcohols suitable for the invention are typically selected from the group consisting of mannitol, xylitol, maltitol, inositol and lactitol, as well as mixtures of these components. Examples are sorbites, Meozog

RIOOT, bogbideh RIE666VO and bogrodet E ipez Stuziaiiipe Zogoyo!, available from Nodieyce Egehev, Segeviag and 5RI

Roiuoiz Ips., respectively Mayizogo ROO (maltitol) is available from Nodiece Egege5, Huiyo! SM5O, Egisioip SM (fructose) and I asiyo! SM5BO is available from Juapizso Zmeeepegv, Isotaia, Isotaia 5T-RE, Sa Tadayuse and manite are available from Raiaipia Apia Boodz and Nodiece, hegez, respectively. Additional examples of suitable saccharide-based binding/sweetening agents include sucrose, dextrose.

In a specific embodiment, a tablet suitable for the invention may include a mixture of sorbitol and xylitol. In such cases, the weight ratio of sorbitol to xylitol is normally in the range of about 1:0.1 to about 1:1.5, for example, about 1:1. A mixture of isomalt and xylitol is also available, and in such cases the weight ratio of isomalt to xylitol is normally in the range of about 1:0.1 to about 1:1.5, for example about 1:1.

The following paragraph provides a description of calcium-containing compounds. However, as mentioned above, the calcium-containing compound for use in the roller compaction process in accordance with the invention has a regular particle shape, for example, specific categories of calcium salt quality, such as calcium carbonate. In a preferred aspect, the calcium salt is calcium carbonate, namely with a shape and average particle size that corresponds to the parameters of 5sogaije 18 or Megec 2064. In a specific variant, the calcium carbonate is 5sogaije 1B or Megek 2064

However, the aforementioned calcium carbonate can be used in the form of a premix with other calcium-containing compounds, for example, such as the compounds listed in the next paragraph, specifically, calcium citrate, calcium lactate, calcium phosphate, including tricalcium phosphate, calcium gluconate, calcium bisglycinate, calcium citrate maleate , hydroxyapatite, including solvates, as well as mixtures of the specified components.

Normally, the content of a calcium-containing compound with a regular particle shape in a tablet is in the range of from about 4095 to about 9595 (wt), for example, from about 4595 to about 9595 (wt), from about 5095 to about 9595 (wt), from about 5595 to about 9095 (wt) or at least about 6595 (wt), at least about 70925 (wt) or at least about 7595 (wt).

Due to the careful selection of the calcium-containing compound and the sugar alcohol in combination with one or more suitable pharmaceutically acceptable excipients, a tablet can be obtained that has a suitable taste and mouthfeel.

Accordingly, it is possible to obtain a tablet which is stable when stored in open Petri dishes at 25°C and 6095 relative humidity (RH) for 1 week or more, for 2 weeks or more, for 3 weeks or more, for 4 weeks or more, for 1 month or more, for 2 months or more, or for 3 months or more, i.e., regulatory requirements can be met with regard to stability for the purpose of dispensing with a dispensing machine.

The tablet of the invention is also stable when stored in a closed container, for example, the tablet is stable at 25°C and 6095 relative humidity for 6 months or more, for example, for 8 months or more, for 10 months or more, for 1 year or more , for 1.5 years or more or for 2 years or more or for 5 years or more and/or the tablet is stable when stored in a closed container at 30°C and 6595 relative humidity for 2 months or more, for example, for 4 months or more, for 6 months or more, for 1 year or more, and/or the tablet is stable when stored in a closed container at 40°C and 7595 relative humidity for 1 month or more,

for example, for 2 months or more, or for 3 months or more, or for 6 months or more, i.e. it is possible to meet the standard regular stability requirements.

Taking into account the stability, the following parameters are important: i) resistance to crushing, i) abrasion, i) appearance and/or i) water sorption

As mentioned above, chewable tablets cannot normally meet the above requirements. In addition, tablets according to the invention are also designed in such a way that they are suitable for swallowing. This requires that the tablets also meet certain disintegration and dissolution requirements, i.e. tablet requirements that give the patient the freedom to choose how he/she wants to consume the tablet (ie, chewing, sucking or swallowing), which is much more conducive to compared to tablets that are prescribed, for example, for swallowing.

Accordingly, tablets must also be stable from the point of view of: m) disintegration, and mi) dissolution.

However, the most difficult task from this point of view is to design tablets in such a way as to give the person in need the freedom to choose between chewing, sucking or swallowing, because it is almost impossible to design tablets that meet the requirements for disintegration and dissolution without the use of a disintegrant. In general, chewable tablets are formulated without any need for a disintegrant, which is an advantage since disintegrants contribute to off-tastes or mouthfeel. Thus, the development of tablets containing one or more disintegrants that have a good taste and an acceptable mouthfeel is not a simple or easy task for one skilled in the art.

Crush resistance and abrasion resistance are important to ensure the tablets are sufficiently strong to withstand dispensing with a dose dispensing machine. In addition, in this context, crush resistance and abrasion should not change significantly during the storage period. If the crush resistance becomes too high, it becomes difficult for the patient to chew the tablets, if it becomes too low, the tablet breaks or disintegrates, and if the abrasion resistance is too high, the tablets are brittle and excessive amounts of dust are generated during the filling of the dosing machine or during the normal cycle of the tablet , for example in patients.

Accordingly, the present invention provides tablets that have a crush resistance in the range of about 40 to about 150N, for example, from about 50 to about 140N, from about 60 to about 140N, or from about 70 to about 140N. The tablet crush resistance changes by at most 5095, for example at most about 4095, at most about 3095, at most about 2095, at most about 1595, at most about 1095, or at most about 595 over a time period beginning after the passage of 5 days storage and lasts for the entire remaining storage period, i.e. at least 1! week In this context, the term "after x days of storage" means x days after storage under the specified conditions, and the term "storage period" means storage under the specified conditions for the specified period of time.

Additionally, the tablets have an erodibility of at most about 595, e.g., at most about 495, at most about 395, at most about 295, at most about 195, at most about 0.595, or at most about 0.195 during the storage period, and/or the tablet erodibility changes by at most 5095, e.g. , at most about 4095, at most about 3095, at most about 2095, at most about 1595, at most about 1095, or at most about 595 during a time period beginning after 5 days of storage has elapsed and continuing throughout the remaining storage period .

Another stability problem is chipping, which can also be avoided or reduced with the present invention

Regarding the appearance, it is determined by visual inspection of the tablets. Tablets are considered stable if they do not change color and a grayish color does not appear on the surface of the tablet, or no coloration is observed during the test period (storage period).

As mentioned above, the tablet according to the invention should not absorb water to a large extent. Thus, the water sorption of the tablet is at most about 595 at 25°C and 6095 RH, for example, at most about 495, at most about 395, at most about 295, at most about 195, at most about 0.595, or at most about 0.195. tablet at 25°C and 6095 RH changes by at most 5095, such as at most about 4095, at most about 3095, at most about 2095, at most about 1595, at most about 1095, or at most about 595 during the storage period. Water sorption is measured using the method of dynamic water sorption.

As mentioned above, there are certain requirements that must be met if the tablets are intended to be swallowed. These requirements ensure that the active substance is available for absorption after administration and that changes in the tablets during storage do not result in changes in bioavailability. The disintegration time requirement ensures that the tablet disintegrates into small particles and the dissolution time requirement ensures that the active substance is released from the tablet and can be dissolved in the surrounding liquid. Accordingly, the tablet according to the invention has a disintegration time determined in accordance with the requirements of the European Pharmacopoeia of at most about 30 minutes, for example at most about 15 minutes. In contrast to ordinary chewable tablets, tablets according to the invention can be covered with a very thin hydrophilic coating. In cases where the tablets are coated, the disintegration time may be at most 30 minutes, while the disintegration time for uncoated tablets is usually at most 15 minutes.

The decay time is stable upon storage and accordingly the decay time changes by at most 5095, for example at most about 4095, at most about 3095, at most about 2095, at most about 1595, at most about 1095, or at most about 595 during a period of time that begins after 5 days of storage and continues throughout the remaining storage period.

With respect to dissolution time, at least 5095 (wt), for example at least 6095 (wt), at least about 7095 (wt), at least about 7595 (wt), or at least about 8095 (wt) of the calcium-containing compound is released at most within about 2 hours, for example, at most about 1.5 hours, at most about 1 hour, at most about 45 minutes, or at most about 30 minutes.

In addition, the dissolution time, measured as the time to release 6095 (w/w) of the calcium-containing compound in the test according to the requirements of the US Pharmacopoeia, varies by at most 5095, for example, at most about 4095, at most about 3095, at most about 2095, at most about at 1595, at most about 1095, or at most about 595 for a period of time that begins after 5 days of storage and continues throughout the remaining storage period.

As can be seen from the above, the present invention solves the problem of providing chewable tablets with an acceptable taste (whereas the tablets can also be sucked or swallowed) and with mechanical properties and size suitable for use as tablets for dispensing by means of a dose dispensing machine.

Overall, improved results and reduced costs are some of the benefits of using a dispensing machine, which can achieve, for example: (i) reduced dispensing time, which increases staff efficiency and frees up staff to perform other functions, and (ii) reduced error rates. prescribing, dispensing and/or administration, (ii) improving patient care through clearly labeled single/multi-dose packages that help patients receive the right medication at the right time, and/or (ii) reducing medication waste.

As mentioned above, the regulatory requirements for tablets dispensed by dosing machines are relatively high and may vary from country to country in terms of application, drug type, stability, etc.

Currently, there are three important types of machines for dose distribution on the market, namely Tozpo type of machines Maip-

Trade 2441 CE. This machine dispenses doses in small plastic bags and dispenses up to 244 different compositions. Another type of Maiip-Torg 4001 SE distributes doses of up to 400 different compositions at the same speed as

Maip-Torga 2441 CE (45 bags/minute)

Ashotei Tesppoiodiez Yps, USA, has, for example, the ATO 212 type on the European market. This machine dispenses doses in small plastic bags and doses and dispenses up to 212 different compositions. The machine packs 25 bags/minute. Other recently released types are improved in terms of the number of different compositions to be packed (330 or 520) and the speed is increased to 60 bags/minute.

Nucirepip Meayisa!I so. (I have a machine for dispensing doses, АТОРО5, which dispenses doses in small plastic bags and dispenses up to 352 different compositions. The speed is 60 sachets/minute. In addition, new machines have been developed (АТОР5 О0ОМ-50051Й and АТОРБ5 ОМ-35251), which release up to 500 different compositions at the same speed (60 bags/minute).

Due to the different sizes and shapes of tablets and capsules, the machines are equipped with different types of cassettes and rotary parts that ensure that only one tablet or capsule is dispensed at a time. The main body of the cassettes is reliably protected from light, it is impervious to dust and moisture, thus, the cassettes are well suited for storing the medicine. Cassettes cannot be mixed up thanks to the safety lock.

Tablets and capsules will not be stored in cassettes for more than a certain period of time to guarantee the quality of the compositions. The machines will notify users if a track has been stored on tapes for more than this period of time.

Considering the size of the tablets, the following requirements must be met to ensure that the tablets can be packaged by the dosing machine: The requirements are dynamic and may change over time.

Round tablet day it

Hey and

M

Length/Diameter ibh sk sk

The thickness of the GSHNVOI is 01 m

Crowd M - maximum 14.0 9.4

. Minimum 1

Nuirzpip - 2 Z

Maximum 3.2 6.7

Minimum 4.6 2.2

Atsuotea Tesi. - and "

Maximum 14.0 7.0

Oval tablet

GE

Zone EZ 1

Shchi chen

Z ni yi hi Kh

Length/Diameter re and i i i i i i i X m"

M i YAKU duv Novo, pu

Ko A Wo N

N EK receive 1 h l skosyu od i ra y

Thickness

Distributor Interval Length (mm) Thickness (mm) Width (mm

Minimum

Tozpo -

Maximum 21.5 7.5 7.5 . Minimum 2.7 4

Nutsirgpipe - 8.5 "0

Maximum 20.0 7.7 10.0

Minimum 6.9 2.2 4.6

Acyutea Thesi. - " " '

Shotea Tes Maximum 21.0 75 11.7

The above measurements for a round or oval tablet can be changed and still fit the specified dosing machine. The experiments conducted by the inventors showed that a variation in the interval of 2095, preferably 1095, is acceptable. In terms of size, one of the main challenges faced by the inventors was reducing the thickness of the tablets. This has been solved by using a suitable combination of the active ingredient(s) and pharmaceutically acceptable excipients, as well as by carefully selecting the appropriate particle size and/or crystal shape of the calcium-containing compound, the properties of the excipients and the method of manufacture.

It is important that the tablets do not generate dust and, as mentioned above, the tablets must be strong enough to withstand the mechanical stress that occurs when using a dispensing machine.

The inventors have discovered that it is possible to apply a thin film coating to the tablets, for example to increase the ability to swallow, or to minimize any problems associated with dust or problems with resistance to crushing or attrition . To that end, it should be noted that the application of a film coating does not solve the significant problems in terms of resistance to crushing or abrasion, but it can provide a final push in the right direction. In addition, only a thin film coating should be applied to maintain an acceptable mouthfeel, i.e., the coating may be applied in an amount corresponding to an increase in tablet weight of at most about 2 95 (wt), e.g. at most about 1.595 (wt), at most by about 1 95 (wt.) or in the range of about 0.25 95 to 0.75 95 (wt.) based on the weight of uncoated tablets.

Below are the measurements of tablets containing calcium carbonate present on the market.

Dimensions of tablets containing calcium carbonate 11111117 Length (mm) Height (mm) Width (mm

SaiIsiro5-O for swallowing (oval/in the form of rov'O d | U for 193 5 8.7 capsules

Saisirov-O chewable tablet (round 27171170 1111-11

Sa!sispem chewable tablet (round 11111170 1111-11

Ideoz chewable tablet (square

A calcium-containing compound

The calcium-containing compound, which is contained in the loose material manufactured in accordance with the invention, is a physiologically acceptable calcium-containing compound that has therapeutic and/or prophylactic activity.

Calcium is indispensable for many key functions of the body, both in the form of ionized calcium and in the form of a calcium complex (Satrei! AK. Siip si 1987; 72:1-10). Calcium regulates the behavior and growth of cells. In combination with troponin, calcium controls muscle contraction and relaxation (Ebazpi 5. Rgos A 5os I opa 1980; 207:259-86).

Selective calcium channels are a universal feature of the cell membrane, and the electrical activity of nervous tissue and the release of neurosecretory granules are a function of the balance between intracellular and extracellular calcium levels (Vygdoupe NO. Viospit Viorpuz Asia 1984; 779:201-16). The secretion of hormones, as well as the activity of key enzymes and proteins, depends on calcium. After all, calcium in the form of calcium phosphate ensures the rigidity and strength of the skeleton (Vozkeu AG. Zrhipdeg, 1988:171-26). Since more than 9,995% of the body's total calcium is found in bones, skeletal calcium also serves as the primary long-term calcium reservoir.

Calcium salts (such as calcium carbonate) are used as a source of calcium, especially for patients at risk of osteoporosis. Moreover, calcium carbonate is used as an acid neutralizing agent in antacid tablets.

As mentioned above, calcium performs many important functions in the body of mammals, specifically humans.

In addition, in many animal models, chronic low calcium intake leads to osteopenia.

Osteopenia affects the ethmoid (spongy) bone to a greater extent than the cortical bone and may not be completely eliminated by calcium supplements. If the animal is growing, reduced calcium intake leads to growth arrest. In preterm human neonates, the higher the calcium intake, the more pronounced the increase in skeletal calcium gain, which, if high enough, can be equivalent to gestational calcium retention. During growth, chronic calcium deficiency causes rickets. Calcium supplements to the diet of healthy children, both in the prepubertal and postpubertal periods, lead to an increase in bone mass. The higher the calcium intake in adolescents, the greater the retention of calcium, with the highest retention occurring immediately after the first menstruation. Overall, these data indicate that in children and adolescents who are considered to have adequate calcium intake, bone mass can be optimized with additional calcium supplementation. The mechanisms involved in optimizing bone calcium deposition during growth are unknown. They probably represent natural properties of the mineralization process that ensures optimal osteoid calcification if the calcium supply is high. The factors responsible for growth arrest in calcium-deficient states are also unknown, but they appear to involve growth factors that regulate skeletal size.

In adults, additional use of calcium reduces the degree of age-related loss of bone mass (Oamzhvop-Nidnez V.

At U Siip My 1991; 54: 5274-80). Calcium supplements are important for individuals who are unable or unwilling to consume optimal amounts of calcium from food. In addition, calcium supplements are important for the prevention and treatment of osteoporosis, etc.

In addition, calcium can have an anti-cancer effect in the colon. Several previous studies have shown that a diet high in calcium or taking calcium supplements is associated with a reduced incidence of colorectal cancer. There is increasing evidence that calcium in combination with acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of colorectal cancer.

Recent scientific studies indicate that calcium may alleviate premenstrual syndrome (PMS). Some researchers believe that calcium dysregulation is an underlying factor in PMS symptoms. In one study, half of a group of 466 premenopausal women from the United States were followed for three menstrual cycles and received 1,200 mg of calcium supplements daily during the cycle. The final results showed that PMS syndromes were present in 4,895 women who took the placebo and only 3,095 women who received the calcium pills.

Calcium salts, for example, calcium carbonate, are used in tablets and due to the need for a high dose of calcium, such tablets are often in the form of chewable tablets. Formulating chewable tablets containing a calcium salt that have a pleasant taste and acceptable mouthfeel without the characteristic overpowering chalky taste or feel is a challenging task.

Calcium-containing compounds for use in accordance with the invention can be, for example, calcium bisglycinate, calcium acetate, calcium carbonate, calcium chloride, calcium citrate, calcium citrate maleate, calcium cornate, calcium fluoride, calcium glubinate, calcium gluconate, calcium glycerophosphate, calcium stearate and tricalcium phosphate. Other sources of calcium can be water-soluble calcium salts or complexes, such as calcium alginate, calcium-EDTA, etc., or organic compounds that contain calcium, for example, calcium organophosphates. The use of bone meal, dolomite, or other unrefined sources of calcium is not recommended because such sources may contain lead and other toxic contaminants.

However, such sources may be suitable if they are purified to the desired degree.

Calcium-containing compounds can be used alone or in combination with other calcium-containing compounds.

Of particular interest are calcium bisglycinate, calcium acetate, calcium carbonate, calcium chloride, calcium citrate, calcium citrate maleate, calcium comatose, calcium fluoride, calcium glubionate, calcium gluconate, calcium glycerophosphate, calcium stearate, and tricalcium phosphate. Mixtures of various calcium-containing compounds can also be used. As is clear from the examples in this description, calcium carbonate is particularly suitable for use as a calcium-containing compound, in addition, calcium carbonate has a high calcium content.

The subject of special interest is calcium carbonate.

Typically, a tablet made in accordance with the invention includes an amount of calcium-containing compound corresponding to from about 100 to about 100 mg of calcium, for example from about 150 to about 800 mg of calcium, from about 200 to about 700 mg of calcium, from about 200 to about 200 mg of calcium or from about 200 to about 500 mg of calcium.

Calcium carbonate

Calcium carbonate can exist in the form of three different crystal structures: calcite, aragonite, and valerite.

From the point of view of mineralogy, they are specific mineral phases associated with the different arrangement of calcium, carbon and oxygen atoms in the crystal structure. These different phases affect the contours and symmetries of the crystal forms. For example, calcite is available in four different forms - scalenohedral, prismatic, spherical and rhombohedral - and aragonite crystals can be obtained as, for example, single or clustered needle-shaped crystals. Other shapes are also available, for example, cubic shapes (Zsogaijye 1A - B from 5soga).

As shown in the examples in this description, a particularly suitable quality category of calcium carbonate is calcium carbonate with an average particle size of bOm or less, for example, 5HOm or less or 40m or less.

In addition, the quality category of calcium carbonate, which has a bulk density of less than 2g/ml, is of interest.

Calcium carbonate 2064 Megsk (available from Megk, Juaptviadi, Germany), which has an average particle size of 10-0µm, an apparent bulk density of 0.4-0.7//ml, and a specific surface area of 0.Zm2/g.

Calcium carbonate 2069 Megsk (available from Megk, Juaptviadi, Germany) which has an average particle size of about 3.9 µm and an apparent bulk density of 0.4-0.7 g/ml.

Zsogaye TA (available from bsog U/Aiguidap, ZA, France) has an average particle size of 5-20 µm, an apparent bulk density of 0.7-1.0 g/ml and a specific surface area of 0.bm/g.

Zsogaye 18 (available from 5soga U/aiguidapi, 5A, France) has an average particle size of 10-25µm, an apparent bulk density of 0.9-1.2g/ml and a specific surface area of 0.4-0.bm2/g.

Zsogaye 1A -- B (available from 5soga Ouaiguidapie, ZA, France) has an average particle size of 7-25μm, an apparent bulk density of 0.7-1.2g/ml and a specific surface area of 0.35-0.8mg/g.

Rpagtasai!b I I. (available from Spg. Napzep. Mapazhap Mem Uegwie I) has an average particle size of 12-16 μm, an apparent bulk density of 1.0-1.5 g/ml and a specific surface area of 0.7 m2/g. zZshgsa! N, Zshtgsa! And Zshgsa! M (available from Zresiayu Mipega!5, VemShiepet, Repzuimapia); Zishtsa! It has an average particle size of approximately 4 μm, an apparent bulk density of 0.78-0.96 g/ml, 9 hgsa! It consists of scalenohedral crystals; zZshgsai! H has an average particle size of approximately 4 μm, an apparent bulk density of 0.48-0.61 g/ml. zZshhesai E has an average particle size of approximately 2.5 microns, an apparent bulk density of 0.32-0.4Zg/ml.

Zshhsa! M has an average particle size of approximately 7μm, an apparent bulk density of 0.7-1.0g/ml and a specific surface area of 1.0m2/g.

Mmiknai 10, 5RI 15, 40 and 65 (available from Rhomepsaié, Rhomepsaié, France):

Mmicpaite 10 has an average particle size of 1Ωm,

Press 5RI. has an average particle size of 20 μm,

Mmicpait 15 has an average particle size of 17 μm,

Mmikpaig 40 has an average particle size of ZOμm, an apparent bulk density of 1.1-1.5g/ml, mikpat 65 has an average particle size of 0μm, an apparent bulk density of 1.25-1.7g/ml.

Otuarigue 35 (available from Otuia 5.A.5., Raieve, France) has an average particle size of 5-33µm and a specific surface area of 2.9m2/g.

Zosa! P2RNM (available from Boimau, Belgium, Belgium) has an average particle size of 1.5 µm, an apparent bulk density of 0.28 g/ml, and a specific surface area of 17.0 m2/g.

Saisi Ryge 250 Neamu, Saisi Ryge 250 Ehiga Neamu and Saisi Ryge SS HO 212 with an average particle size of 10-33 Ωm, an apparent bulk density of 0.9-1.2g/ml and a specific surface area of 0.7m2/g (available from Rapisier

Pbupatis Ips., 5. And fathers, Mopiapa).

The content of the calcium-containing compound in a tablet prepared in accordance with the present invention is in the range of from about 4095 to about 10095 (wt), for example from about 4595 to about 9895 (wt), from about 5095 to about 9595 (wt), from about 5595 to about 9095 (wt) or at least about 6095 (wt), at least about 6595 (wt), at least about 7095 (wt), or at least about 7595 (wt).

A normal dose of calcium for therapeutic or prophylactic purposes is from about 350 mg (for example, for a newborn) to about 1200 mg (for a lactating woman) daily. The amount of calcium-containing compound in the tablets can be adjusted so that the tablets will be suitable for administration 1-4 times a day, preferably once or twice a day.

As mentioned above, the granulate obtained by the method according to the invention can be used as received, but it is also highly suitable for further processing to obtain solid dosage forms, for example, tablets, capsules or sachets.

The examples of this description provide guidance on which parameters are important to take into account and how to select a suitable kit for the manufacture of chewable tablets or tablets for swallowing, respectively. One skilled in the art will understand how to adjust the composition and various process parameters to obtain the desired calcium-containing product.

In the manufacture of tablets, it is often necessary to add one or more pharmaceutically acceptable excipients (eg, lubricants) to avoid adhesion and/or increase the fluidity of the resulting granulate. Accordingly, the method may also include the stage of mixing the obtained granulate with one or more pharmaceutically acceptable excipients.

In case it is desirable to include other active substances than the calcium-containing compound, the method may also include the step of adding one or more therapeutically, prophylactically and/or diagnostically active substances to the resulting granulate.

Such substances include one or more nutrients, for example, one or more vitamins or minerals. In a specific variant, the further active substance is vitamin 0, for example, vitamin OZ,

vitamin 02 or their derivatives.

Vitamin 0 or other active substances

A granule or tablet made in accordance with the invention may include an additional therapeutically and/or prophylactically active substance, or may contain one or more nutrients, for example, one or more vitamins or minerals. Of particular interest are, for example, vitamin B, vitamin C, vitamin O and/or vitamin K and minerals such as zinc, magnesium, selenium, etc.

Of particular interest are, for example, vitamin B, vitamin C, vitamin O and/or vitamin K and minerals such as zinc, magnesium, selenium, etc. Of particular interest are one or more compounds of vitamin OJ, such as vitamin 02 (ergocalciferol) and vitamin OH (cholecalciferol), including dry vitamin 03, 100

SMU5 is available from Rospe, and dry vitamin OZ 100 SER is available from VABE.

In addition to influencing calcium metabolism and skeletal homeostasis, vitamin O is involved in the regulation of several major systems in the body. The action of vitamin O is mediated in the genome by a complex formed by 1,25-(OH)vitamin Y, which is mainly produced in the kidneys, with the vitamin Y receptor (VY). The latter is widespread in many types of cells. 1,25-"OH)2 vitamin O/UOV complex plays an important regular role in cell differentiation and in the immune system. Some of these effects probably depend on certain tissues, other than the kidney, to produce 1,25-(OH)vitamin O locally and act as paracrine structures (Adat vi a). Epdoshypoiodu 1996; 137:4514-7).

In humans, vitamin O deficiency leads to rickets in children and osteomalacia in adults. The main anomaly is a delay in the rate of mineralization of the osteoid, as it is carried out by the osteoblast (Reasosk M. I opdop

Imiposiope, 1993:83-118). It is not yet clear whether this delay is a consequence of the failure of the 1,25-(OH)vitamin O-dependent mechanism in the osteoblast or reduced calcium and phosphate stores secondary to malabsorption or a combination of both factors. The delay in mineralization is accompanied by a decrease in the intake of calcium and phosphate, pronounced secondary hyperparathyroidism with hypocalcemia and hypophosphatemia, and increased bone turnover.

Vitamin O deficiency, as a preclinical phase of vitamin O deficiency, also causes decreased calcium intake and secondary hyperparathyroidism, although to a lesser degree than that seen in deficiency. If the condition remains chronic, osteopenia occurs. The biochemical process underlying the specified state of calcium deficiency is probably an inappropriate level of 1,25-(OH)vitamin O due to the reduction of its substrate 25-OHO (Rhapsiv VM ei ai. Yeig U Siip Ipmezi 1983; 13:391- 6). Vitamin O deficiency is most often found in the elderly. Serum 25-OH vitamin O levels decrease with age due to decreased exposure to sunlight and possibly due to decreased synthesis in the skin. In addition, in old age, the condition is aggravated by a decrease in calcium intake and a paradoxical decrease in calcium absorption. A decline in kidney function with age leads to a decrease in kidney production of 1,25-(OH)vitamin O, which may be a contributing factor. A number of studies have been conducted to study the effect of additional consumption of vitamin O on the reduction of bone mass in the elderly. Some of them were conducted without additional calcium intake, and some with additional calcium intake. Research results indicate that although additional intake of vitamin U is necessary to correct deficiency and insufficiency, it is even more important because the skeleton requires additional calcium intake, since the main skeletal defect is calcium deficiency. In the literature based on clinical trials, recently obtained data indicate a trend towards the need for higher doses of vitamin O in elderly patients (Sotrziop UE. VMU 1998; 317:1466-67). An open quasi-randomized study of annual injections of 150,000-300,000 IU of vitamin O (equivalent to approximately 400-800 IU/day) showed a significant reduction in the overall incidence of fractures, but not in the incidence of hip fractures in treated patients (Neikippeito NU ei ai.

Saisii Tizvye Ipi 1992; 51:105-110).

As follows from the above, the combination of calcium and vitamin O is of interest. Recommended

The daily allowances (DAA) for calcium and vitamin O intake are as indicated below (European Commission. Report on osteoporosis in the European Community. Actions for prevention. Office of Official Publications

of the European Community, Luxembourg, 1998):

Groups Age (years) Calcium (mg)" Vitamin OZ. 0-0.5 400 10-25

Newborns 0.5-1.0 360-400 10-25 1.0-3.0 400-600 10

Children 4.0-7.0 450-600 0-10 8.0-10 550-700 0-10 11-17 900-1000 0-10

Men 18-24 900-1000 0-15 25-65 700-800 0-10 65 700-800 10 11-17 900-1000 0-15 18-24 900-1000 0-10

Women 25-50 700-800 0-10 51-65 800 0-10 65 700-800 10

Pregnant women 700-900 10

Lactating women 1200 10 " The recommended daily intake of calcium varies from country to country and has been re-evaluated in many countries.

Vitamin O is very sensitive to moisture and undergoes decomposition. Therefore, vitamin OO is often administered in a protective matrix. Accordingly, in the manufacture of tablets containing vitamin YO, it is most important that the compression force applied at the tableting stage does not reduce the protective effect of the matrix and, thus, does not reduce the stability of vitamin YO. To this end, it has been proved that the combination of the various ingredients in a granulate or tablet made in accordance with the invention is very suitable in those cases where vitamin Y is also introduced into the composition, since a relatively low pressing force can be used in the tableting process, and all to obtain tablets with suitable mechanical resistance (resistance to crushing, abrasion, etc.).

Accordingly, the pressing step is carried out with a pressing force of at most approx

B5OKN, at most about 40kN, at most about 30KkN, at most about 25KkN, or at most about 2O0kN, when tablets having an oval shape with a length of about 19mm, a width of about 9.4mm and a final height of about 5.5-8mm are obtained. A person skilled in the art will know how to determine the appropriate compression force if tablets with dimensions that deviate from the above are obtained.

As indicated above, a tablet containing vitamin O is included which meets the following stability requirements:

After storage in open Petri dishes at 25°C and 6095 relative humidity for 1 week or more, for example, for 2 weeks or more, for 3 weeks or more, for 4 weeks or more, for 1 month or more, for 2 months or more or for 3 months or more, the vitamin YO content should vary by at most 2095 (wt), for example at most about 1595 (wt), at most about 1095 (wt), or at most about 10 595 (wt) during the period storage.

After storage in a closed container at 25°C and 6095 relative humidity, the tablet is stable in terms of vitamin ХO content for b months or more, for example, for 8 months or more, for 10 months or more, for 1 year or more, for 1 .5 years or more or for 2 years or more and/or the tablet is stable when stored in a closed container at 30°C and 6595 relative humidity for 2 months or more, for 4 months or more, for 6 months or more, for 1 year or more and/or the tablet is stable when stored in a closed container at 40°C and 7595 relative humidity for 1 month or more, for example, for 2 months or more, for 3 months or more, i.e. the vitamin O content of the tablet must change at most 2095 (wt), for example at most about 1595 (wt), at most about 1095 (wt), or at most about 595 (wt) during the storage period.

In a specific embodiment, at least 5095 (wt), for example, at least 6095" (wt), at least about 7095 (wt), at least about 7595 (wt), or at least about 8095 (wt) of vitamin SO is released at most within about 2 hours, for example, at most about 1.5 hours, at most about 1 hour, at most about 45 minutes, or at most about 30 minutes. In addition, the dissolution time, measured as the time to release 6095 (wt) of vitamin O from the tablet in a dissolution test according to the requirements of the US Pharmacopoeia, varies by at most 5095, for example, at most about 4095, at most about 3095, at most about by 2095, at most about 1595, at most about 1095, or at most about 595 during the time period that begins after the 5 days of storage have passed and continues throughout the remaining storage period.

In a specific embodiment, the invention provides a tablet including (i) a calcium-containing compound as an active substance, (ii) vitamin O and (ii) optionally one or more pharmaceutically acceptable excipients or active substances.

More specifically, the tablet may include i) at least 200mg of a calcium-containing compound (normal range 200-1500mg), ii) at least 5mcg of vitamin O (normal range 5-10Omkg, mcg - 40IU), ii) optionally one or more pharmaceutically acceptable excipients substances or active substances.

In a specific embodiment, the invention provides tablets comprising i) from about 5095 to about 9095 (wt) of a calcium-containing compound, and) from about 0.0002995 to about 0.012295 (wt) of vitamin O and i) optionally one or more pharmaceutically acceptable excipients or active substances, provided that the total number of ingredients corresponds to approximately 10095 (w/w).

In particular, the tablet may include i) from about 5095 to about 9095 (wt) of a calcium-containing compound, i) from about 5 to about 4095 (wt) of a sweetening agent, and i) from about 0.1295 to about 4.995 (wt) of a vitamin Oh, including the protective matrix, they) optionally one or more pharmaceutically acceptable excipients or active substances, provided that the total number of ingredients corresponds to approximately 10095 (wt). In a specific embodiment, the tablets have a shape and size substantially as shown in figure C in this description. This form is specially designed to easily break the tablet into two halves of approximately the same size, that is, those that contain substantially the same amount of calcium. Breaking can be achieved by placing the tablet on a flat surface, for example, a table, followed by pressing, for example, two fingers simultaneously on each end of the tablet. This is possible due to the fact that the tablet contacts the table at only one point.

Production of tablets according to the invention

In general, the tablets of the invention may be manufactured by any suitable method known to a person skilled in the art. The process may involve wet granulation, for example in a high shear mixer or fluidized bed apparatus, for example roller compaction followed by pressing the resulting powder into tablets, or may be a direct pressing process without granulation. One of skill in the art will know how to use the various methods, not necessarily with the instructions of Netipdiopye Rnaptaseciis! Zsieepsez, 28

Eh.

Pharmaceutically acceptable excipients

In this context, the term "pharmaceutically acceptable excipient" means any material that is inert in the sense that by itself it does not substantially exert any therapeutic and/or prophylactic effect. A pharmaceutically acceptable auxiliary substance can be added to the active substance of the medicinal product in order to create the possibility of obtaining a pharmaceutical composition that has acceptable technical properties.

The calcium-containing compound is normally mixed with one or more pharmaceutically acceptable excipients before pressing into tablets. Such excipients include those commonly used in the formulation of solid dosage forms, such as excipients, binding agents, disintegrants, lubricating agents, flavoring agents, coloring agents, including sweetening agents, pH adjusting agents, buffering agents, stabilizing agents, and etc. The following are examples of excipients suitable for use in a tablet in accordance with the present invention.

Sweetening agents

Examples of suitable sweetening agents include dextrose, erythritol, fructose, glycerol, glucose, inositol, isomalt, lactitol, lactose, maltitol, maltose, mannitol, sorbitol, sucrose, tagatose, trehalose, inulin, and the like. Sorbitols such as Meosogo P100T, bogbideh RI666VO and bogrodet Ripez Stguziale zZogrioY are available from Nkodiece Egeges, Segevziag and RI Roiuov Ips., respectively. Maiyzogo ROO0 (maltitol) is available from Nodiece Egegev5, Huyo! SM5O, Egpisioip SM (fructose) and aso! CM5O are available from Yuapivso

Zmeviepeg5, Izotai 5T-RE, Sa Tadaze, and mannitol are available from Rayaipia, Aia Rooa5z, and Nodieeye, Egegev, respectively. Sorbitol has a sweetening effect (compared to sucrose) at a level of 0.55; maltitol has a sweetening effect "1; xylitol has a sweetening effect 1; isomalt has a sweetening effect "0.5, etc. The sweetening effect can be a parameter from the point of view of choosing individual sweetening agents. Thus, if it is desired to reduce the mass and volume of the tablet, the choice of a sweetening agent with a more intense sweetening effect is suitable.

Artificial sweetening agents

Acesulfame potassium, aspartame, cyclamic acid, cyclamate salt (eg, calcium cyclamate, sodium cyclamate), neohesperidine dihydrochalcone, neohesperidine hydrochloride, saccharin, saccharin salt (eg, ammonium saccharinate, calcium saccharinate, potassium saccharinate, sodium saccharinate), sucralose, thaumatin and mixtures of the specified components.

Flavorings

Apricot, Lemon, Lemon/Lime, Lime, Orange, Tangerine, such as Argosoi 501.110 AROB51, I etop 501.051

TROB5I1, Hetop 501.162 AROBB51, I etop// ite 501.053 TROB5B1, I ite 501.054 TROBB1, Ogapde 501.071 AROBBI1,

Ogapde TROBB1, Ogapde 501.434 ROB551, Mapaagipe 501.AROB51, I etop Yuigagote 501.282 TON 091, available from

Rigtepisn, Kegrepp, Germany or diisu Getop Riamoshhipd 73602, available from TazieTesi, Vigiz!, England or

Getop I ite Riamogyg Reptzeai 11029-31, Getop Riamoig Regtagzeai! 12028-31, | etop Riamoig Ogadwzea! 96918-71, available from Simandap Zspmei2 AS, Katria!, Switzerland or 1 etop Riahoig Romzhdeg 605786, Getop Riamoszg

Romaeeg 605897 is available from Egeu -- Iash Shtry, Nepzivdi-Oi2bygo, Germany.

Disintegrants

Alginic acid - alginates; calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium crospovidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), cellulose derivatives such as hydroxypropyl cellulose with a low degree of substitution (for example, IN 11.1 H 20, IN 21, IN 22, IN 30, IN 31, IN 32 , available from ZPip-Eiiva

Spetis! So.) and microcrystalline cellulose, polacrylin sodium or potassium, polyacrylic acid, polycarbophil, polyethylene glycol, polyvinyl acetate, polyvinylpyrrolidone (for example, RoimidopF SI, RoimidopF

SI-M, CoiyidopeF SI, Rouriazadopeb XI, RoiuriazdopeF XI-10); sodium carboxymethyl starch (eg

Riitodecyu and EchrioiabF), croscarmellose sodium (ie, a cross-linked polymer of sodium carboxymethylcellulose; for example, As-Oi-50I2), sodium starch glycolate, various types of starch (for example, potato starch, corn starch, and rice starch), pregelatinized starch.

Those skilled in the art will appreciate that compressible tablets preferably disintegrate within 30 minutes, more preferably within 15 minutes, most preferably within 5 minutes; thus, the disintegrant used preferably disintegrates the tablet within 30 minutes, more preferably within 15 minutes, most preferably within 5 minutes.

A loosening agent (for example, a mixture of sodium bicarbonate (carbonate, alkaline, alkaline earth metal) and citric acid (tartaric acid, fumaric acid, etc.)).

Lubricants and lubricating agents

Glidants and lubricating agents may be included, such as stearic acid, metal stearates, talc, high melting point waxes and glycerides, hydrogenated vegetable oils, colloidal silicon dioxide, sodium stearyl fumarate, polyethylene glycols, and alkyl sulfates.

Suitable lubricating agents include talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, and the like.

Fillers/diluents, binding agents

Dextrins, maltodextrins (for example, I odexFf 5 and I odexFf 10), dextrose, fructose, glucose, inositol, erythritol, isomalt, actose (e.g. spray-dried lactose, a-lactose, B-lactose, Tarijosef), various categories of RpagtayuzeFf), Misgoiuse or Eavzy-Riof)), maltitol, maltose, mannitol, sorbitol, sucrose, tagatose, trehalose, xylitol, hydroxypropyl cellulose with a low degree of substitution (for example, !Н11,1Н 20,1 Н21, IN 22, IN 30, IN 31, IN 32, available from ZPip-Eizyza Spetis! So., microcrystalline cellulose (for example, various categories of Amise!F), such as Amise(Ff RNIO1, Amise(F RNIO102 or AmiseI(b RNIO5, EisetafF P100, Etsose!iF, Mimase !F,

Mipd TaiFf and BoikKa-BriosF), various types of starch or modified starch (including potato starch, corn starch, rice starch, pregelatinized starch), polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, agar (eg sodium alginate), calcium hydrogen phosphate, calcium phosphate ( e.g. basic calcium phosphate, calcium hydrogen phosphate) calcium sulfate, carboxyalkyl cellulose, dextrans, dibasic calcium phosphate, gelatin, gum arabic, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, magnesium carbonate, magnesium chloride, methyl cellulose, polyethylene glycol, polyethylene oxide, polysaccharides, e.g. dextran, soy polysaccharides, sodium carbonate, sodium chloride, sodium phosphate.

Surfactants/enhancers

Surfactants can be used, such as: nonionic (eg, polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, polysorbate 120, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, glyceryl monooleate, and polyvinyl alcohol), anionic (eg, sodium docusate and sodium lauryl sulfate), cationic (eg, benzalkonium chloride, benzethonium chloride, and cetrimide).

Fatty acids, fatty alcohols and fatty acid esters, for example: ethyl oleate, sodium oleate, lauric acid, methyl laurate, oleic acid, sodium salt of caprylic acid.

Calcium dioctylsulfosuccinate, potassium dioctylsulfosuccinate, dodecyltrimethylammonium bromide, hexadecyltrimethylammonium bromide, trimethyltetradecylammonium bromide, polyoxyethylene ethers (polyoxyethylene-9-lauryl ether), sodium dodecyl sulfate, sodium dioctylsulfosuccinate, sodium laurate, sodium 5-methoxysalicylate, sodium salicylate; salts of bile acids, for example: sodium deoxycholate, deoxycholic acid, sodium cholate, cholic acid, sodium glycocholate, sodium glycodeoxycholate, sodium taurocholate, sodium taurodeoxycholate; cytoadhesive agents, for example: lectins (for example, agglutinin I usoregvisop Evscepisht, agglutinin of wheat germ, agglutinin Opis Oisois).

M-Acylated amino acids (especially M-I8-(2-hydroxy-4-methoxy)benzoyl|aminocaprylic acid (4-

MOAS), 4-I4-(2-hydroxybenzoyl)amino|butyric acid, sodium M-I|8-(2-hydroxybenzoyl)amino|-caprylate); phospholipids, for example: hexadecylphosphocholine, dimyristoylphosphatidylglycerol, lysophosphatidylglycerol, phosphatidylinositol, 1,2-di(2,4-octadecadienoyl)-zp-glycerol-3-phosphorylcholine, and phosphatidylcholines (for example, didecanoyl-phosphatidylcholine, dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine), phosphatidylphosphatidylcholine, disteylcholine are of special interest; cyclodextrins, for example:

B-cyclodextrin, dimethyl-3-cyclodextrin, y-cyclodextrin, hydroxypropyl-B-cyclodextrin, methylcyclodextrin; specifically, dimethyl-VD-cyclodextrin, methylcyclodextrin is of particular interest; derivatives of fusidic acid, for example: sodium taurohydrofusidate, sodium glycodihydrofusidate, sodium fomfatdihydrofusidate; especially sodium taurodihydrofusidate is of particular interest; others: sodium salts of e.g. glycyrrhizic acid, caproic acid, alkanes (e.g. ahacycloalkanes), amines and amides (e.g. M-methydpyrrolidone, Agope), amino acids and modified amino acid compounds (e.g. acetyl-!-cysteine), polyols (e.g. - carnitine, chloride and -stearoylcarnitine, acylcarnitine, ethylene diamine dihydrochloride, phosphate dihydrofusidate, sodium SAR); especially p-lauryl-beta-O-maltopyranoside is of particular interest, alpha 1000 peptide, MMUU-1000 peptide, which includes at least 95 bmol of aspartic and glutamic acid, royal jelly, probiotics, butyrate, butyric acid, vitamin 02, vitamin OZ, phydroxyvitamin 03, 1,25-vitamin 03, spirulina, proteoglycan, soy hydrolyzate, lysine, lactic acid, di-fructose anhydride, villitol Ca-(lactate), casein hydrolyzate, in particular casein glycomacropeptide, negative ionization of CaCo», acid acetylsalicylic acid, vitamin K, creatine.

Film-forming agents

Film-forming agents for the formation of a hydrophilic film, for example, hydroxypropyl methylcellulose (HPMC) (eg, HPMO E5, HPMC E15), hydroxyethyl cellulose, hydroxypropyl cellulose, polydextrose and maltodextrin, Zerit"mM and Zerittm | P available from Zerris 5.A., Pnappasoatske available from ZPPip- Hey!

Spetisai! Co.

Film additives

Acetylated monoglyceride, acetyl tributyrate, acetyl tributyryl citrate, acetyl triethyl citrate, benzyl benzoate, calcium stearate, castor oil, cetanol, chlorobutanol, colloidal silicon dioxide, dibutyl phthalate, dibutyl sebacate, diethyl oxalate, diethyl alate, diethyl maleate, diethyl malonate, diethyl fumarate, diethyl phthalate, diethyl sebacate, dimethyl succinate, dioctyl phthalate, glycerin, glyceryl tributyrate, glyceryl triacetate, glyceryl betanate, glyceryl monostearate, hydrogenated oil, lecithin, leucine, magnesium silicate, magnesium stearate, polyethylene glycol, propylene glycol, polysorbate, silicone, stearic acid, talc, titanium dioxide, triacetin, tributyryl citrate, triethyl citrate, zinc stearate, wax

The invention is further illustrated by the following non-limiting examples.

Legends to Figures

Figure 1 shows the stability of crush resistance of tablets obtained on the basis of wet granulation.

Figure 2 shows the stability of disintegration of tablets obtained on the basis of wet granulation.

Figure C shows the tablet design.

Figure 4 shows how to divide a tablet according to the design of Figure 3.

Methods

Organoleptic testing 150-6564, Organoleptic analysis - Methodology - Aroma properties profile methods

IBO-5495, Organoleptic analysis - Methodology - Paired comparison test

I5BO-8589, Organoleptic analysis - General guidelines for the design of test rooms

IBO-8586, Organoleptic analysis - General instructions for the selection, training and control of persons carrying out the assessment

Resistance to crushing In accordance with the requirements of the European Pharmacopoeia 2.9.8

Rubability In accordance with the requirements of the European Pharmacopoeia 2.9.7

Disintegration time In accordance with the requirements of the European Pharmacopoeia 2.9.1

Solution In accordance with the requirements of the European Pharmacopoeia 2.9.3

Examples

The following materials were used in the following examples:

Finland

Germany pregelatinized

Netherlands 10000oMO/g

France

Taiwan

Michigan 2910, Pharm. USA XXI, Appendix 2

Zeriyiti P 010 Zerris 5. A., Ragiz, France Powder mixture, it is necessary to add only water to obtain a ready-to-use film

Examples

Example 1

Effect of Different Manufacturing Methods on Calcium Carbonate Tablet Sizes This experiment was conducted on a large scale production with a batch size of approximately 40,000 tablets. The experiment was carried out to investigate whether the technique used to produce the granulate to obtain the product has any effect on the dimensions of the tablets, especially the height of the tablet.

The investigated methods were: i) Wet granulation in a high shear mixer, i) Fluidized bed granulation, and iii) Roller compaction.

Table 1

The composition of the sealing layer

Raw material Batch 1 on Batch 2 on| Party Z na Z and

Lot 4 on 10001 Lot 5 on the torso of the table. torso tab, torso tab, tab. |d) 1000 table 1 | bsogaine IV (predominant 1250.0 1250.0 1250.0 1250.0 1250.0 and IV Vitamnozi 77771711 -1Ї11-Ї1 144 1-1 -

Mayivogo R 90 12000 | 450 |: - | -

Huinoi SMBO 195.01 120.0 19501717 111111

Zogrideh 16680 7-17 - 0117777 -117177711117-111111171 3855

Meovogo RIOOT 7-17 -117- 390.0 2

Ziagop 1500 5аО | 5O | 540 | - | -

Microcrystalline cellulose x pH 101 15.0

Asevtsat Kk 10 | 10 | 170 | sh- | at

OH fAspartame///////// HER -1 1117-1111 -11111110 Her

Flavoring Lemon

CHEM |Flavoring Lemon Granules|i /-/- | | 4 50.68 1-0

HM |Magiyustvarat//// | 65 | 65 | 65 | 60 | 60

KhM |Water Treatment Plant//////777777 1716555 | 655 | 655 | 7350 | - 0001071 Massa tablets | 15650 | 15640 1569.0 1734.08 1725.0

Production of batches 1-3:

Liquid for granulation was obtained by dissolving MI! in KhMI

YM and M were passed through a sieve of appropriate size and mixed with I in a 220 I high shear mixer for 1 minute at a rotor speed of 110 rpm and a blade speed of 1500 rpm. The powder mass was moistened with liquid for granulation at a rotor speed of 110 rpm and a knife speed of 1500 rpm. Wet granulation was continued for 5 minutes at a rotor speed of 220 rpm and a knife speed of 1500 rpm. The wet granulated powder was dried in a fluidized bed until the absolute moisture content did not drop below 0.595.

The rest of the excipients were mixed with the dried granulate.

Batch 4 production:

Liquid for granulation was obtained by dissolving MI! in KhMI

MI was passed through a sieve of appropriate size and mixed with I in a fluidized bed granulator

Schai The powder mixture was granulated by spraying the liquid for granulation on the powder layer during the fluidization process.

The remaining parts of the excipients XII, XIM and XM were mixed with the dried granulate.

Batch 5 production:

IM and M or MI were passed through a sieve of appropriate size along with I or II in a 220 I high shear mixer for 1 minute with a rotor speed of 110 rpm and a blade speed of 1500 rpm. The powder mixture was granulated using a device for roller compaction (Segeiv ZM/-Roiudgap). Roller compaction was carried out with the help of corrugated rollers and control.

Roller compaction was carried out on an installation with corrugated rollers and a control. The key set of parameters was as follows: Gap Width (CM), Force (E), Roller Speed (AB) and Screen Size.

Conditions of roller compaction

VZ, rpm followed by mixing with the rest of auxiliary substances X, XI, XP and XM. For all granulates from series 1-5, tablets were pressed using an Eietze 1090 and a capsule-shaped punch design (9.4mmx18.9mm)

Table 2

Adjusted pill height for series 1-5

Pressing force (kn) Corrected tablet height (height Tablet length tablet/tablet weight) (mm/mg)"10 MM 19.13 19.11

19.13 19.04 19.07

The results show that the lowest tablet height is obtained by wet granulation in a high shear mixer (batch 1-3), the highest tablet height is obtained by roller compaction (batch 5) and the highest tablet height is obtained using fluidized bed granulation (batch 4) .

Example 2

Tablets with different coating materials - distributed using machines for distributing doses

The purpose of this experiment was to test tablets with different types of coating in dose-dispensing machines.

Tablets produced in accordance with series 1, 2 and 3 in Example 1 were obtained. The tablets were covered with a film of hydroxypropylmethylcellulose or berite GR 010 using a laboratory device Sotri-Soaia (Migo) (spraying from above).

Table C

Type of applied film

Film Film Zeriit hydroxypropyl cellulose | (increase in mass increase 0.7595 mass 595

Besio NnN ZNNYA NOYA

Party p MY and POHN

Party p and MOU

The composition of the hydroxypropylmethylcellulose film:

Raw material | in (wt.) 1 Hypromellose E15 07771111 Talc 17771115 "OY Propylene glycol./-:/ //| 05 (ZI

Composition Zeriyt R 010

Raw. | Zs (wt.) 1 Zeriyit R 010

And WHAT about Vodaochishchena.i/- | 88 (

The coating was applied to tablets with standard parameters and the dimensions of the tablets were measured.

Tablet dimensions

Corrected

Force height Length of tablet compression (tablet height (kn) tablet/weight (mm) tablet) mm/mg)"103

Lot 1, without 9.5 19.1 coating

Batch 1, from Russia NO AVAILABLE NOW

Lot 2, from Russia, NOW WE ARE PEARL coating

Tablets were tested in cassettes for two different dosing machines at Aroiekei AB.

UM5 and BRM cassettes, which correspond to the Tov5po dosing machine, and ATS cassette, which corresponds to the Vahieg dosing machine, were collected and tested for tablets.

All coated tablets were accepted for dosing machines. The uncoated batch 1 tablets were very dusty and thus not ideal for this type of equipment. Dust can be avoided by coating the tablets.

Example C

Testing of round tablets in a machine for dispensing doses

The purpose of this experiment was to test the round pill in the dosing machines.

The final granulate in accordance with batch 4 in Example 1 was produced and pressed into tablets using tools for the production of a round tablet of 13.95 mm.

Tablet dimensions

WE are idiots

MM MM

Tablets were tested in cassettes for three different dosing machines at Aroiekei AB.

Tablets were accepted for dosing machines. This fact occurred despite the maximum recommended tablet measurements for three different dosing machines:

MM MM

The fact that tablets may be acceptable for dispensing machines even if they exceed the limits recommended by dispensing machine suppliers illustrates that the decision must be based on actual testing...

Example 4

Stability of calcium carbonate tablets

This experiment was conducted to investigate the stability of crush resistance and disintegration time of tablets in open Petri dishes at a temperature of 257°C/6095 relative humidity. Tablets produced in accordance with Example 1, batch 1, were compared with tablets produced using a mixer with high shear containing sorbitol Tablets produced using fluidized bed granulation were used as a reference preparation to evaluate resistance to crushing.

The production of a granulate containing sorbitol using a high shear mixer was carried out using the following design, composition and manufacturing process:

Design 11111111 Party! | Party? | PartyZ | Party 4

Table 4

Storage

С 11111111111111111бировинаї////77777777777717171717171717111 77171711 Кількість 11111111 Кальціюкарбонат(Зсогаде).д//////7777777771717711111111111111159352 11111111 Сорбіт3вмкмабоїїомкм.///////77777777777171717171111111111111648с 111 повідонк3 77777771

Production: III was dissolved in IM.

They were passed through a 250 μm sieve and mixed with | in a Rieidegh high-shear laboratory mixer (mixing time 1 minute). Dissolved IT was added by spraying and granulation was carried out for 2 or 4 minutes.

The wet granulate was dried in a laboratory fluidized bed dryer using an inlet temperature of approximately 60°C. The granulate was dried to a maximum moisture content of less than 0.595. pressed using a laboratory tablet press Kogesp PH 106, and a punch design in the form of a capsule (9.4mmx18.9mm).

Production of granulate based on a fluidized bed was carried out in accordance with Example 1, batch 4. Tablets were pressed using Mapesiu VZV and a round concave punch of a folding design of 14 mm.

The results of the study are shown in Table 5 (for Example 1, batch 1), in Table 6 (for Example 1, batch 4) and in Figures 1 and 2 for tablets containing sorbitol according to Table 4.

Table 5

Stability of tablets in accordance with Example 1, batch 1 and Resistance to Disintegration time

Time (days) of crushing (H minutes 0 ІІ yush168. | 70 2 sh zh"«'/'"- 77 | v | 898 60 | shyuschBG 92 2 sh | 7159 ( 90 | yuzhsch 86 shЩ (/ 81

Table 6

Stability of tablets in accordance with example 1, batch 4

Time (days) Crush resistance 90117177111111111187

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Claims (20)

1. A calcium-containing tablet comprising a calcium-containing compound with a regular particle shape as an active substance and a pharmaceutically acceptable sugar alcohol having a particle size (0(y;50.5)) of less than about 150 µm, and the tablet having a porosity of less than 20 95. 2. The tablet according to item I, which is characterized by the fact that one or more calcium-containing compounds are in the form of crystals having a specific surface area of less than 1.5 m"/g, for example 1.3 m"/g or less, 1, 1 m"/g or less, 0.9 m"/g or less or 0.7 m"/g or less. 3. The tablet according to item I or 2, which is characterized by the fact that the concentration of pharmaceutically acceptable sugar alcohol is at least 5 wt. about, for example, at least 10 wt. Pho, at least 15 wt. oh, at least 20 wt. 90, at least 25 wt. because or at least 30 wt. 96. 4. A tablet according to any of the previous items, characterized in that the pharmaceutically acceptable sugar alcohol used has an average particle size of at most 150 µm, for example at most 110 µm, at most 100 µm, at most 90 µm, at most 80 µm, at most 70 µm , at most 60 μm, at most 50 μm, such as at most 40 μm, at most 20 μm, such as 10 μm. 5. A tablet according to any of the previous items, which is characterized by the fact that a pharmaceutically acceptable sugar alcohol is used, which has an average particle size in the range from 5 to 150 μm, for example from 5 to 110 μm or from 5 to 80 μm. b. A tablet according to any of the previous items, which differs in that the sugar alcohol is sorbitol, isomalt, xylitol, maltitol, mannitol, inositol, lactitol or mixtures thereof. 7. A tablet according to any of the previous items, which is characterized by the fact that the calcium-containing compound is a calcium salt. 8. A tablet according to any of the previous items, which is characterized by the fact that the calcium salt is calcium carbonate. 9. A tablet according to any of the previous items, which is characterized by the fact that it includes one or more other calcium-containing compounds selected from the group consisting of calcium bisglycinate, calcium acetate, calcium carbonate, calcium chloride, calcium citrate, calcium malate citrate, cornate calcium, calcium fluoride, calcium glubunate, calcium gluconate, calcium glycerophosphate, calcium hydrogen phosphate, calcium hydroxyapatite, calcium lactate, calcium lactobunate, calcium lactogluconate, calcium phosphate, calcium podolate, calcium stearate 1 tricalcium phosphate. 10. A tablet according to any of the previous items, which is characterized in that the amount of calcium-containing compound is from 100 to 1000 mg Ca, for example from 150 to 800 mg, from 200 to 700 mg, from 200 to 600 mg or from 200 to 500 mg Ca. 11. A tablet according to any of the previous items, which is characterized by the fact that the total concentration of one or more calcium-containing compounds is in the range from 40 90 to 99 wt. o, for example from 45 9o to 98 wt. 90, from 50 9o to 95 wt. 90, from 55 90 to 90 wt. up to or at least 60 wt.2o, at least 65 wt. 9o, at least 70 wt. 90. 12. A tablet according to any of the previous items, which differs in that it contains from 60 90 to 95 wt. o calcium-containing compounds and from 5 Uo to 40 wt. o pharmaceutically acceptable sugar alcohol, provided that the amount does not exceed 100 wt. 90. 13. A tablet according to any of the previous items, which differs in that it contains from 60 to 94 wt. 906, for example from 65 9Uo to 80 wt. o calcium-containing compounds, from 5 to 35 wt. 90, for example from 15 to 30 wt. o pharmaceutically acceptable sugar alcohol 1 from I to 15 wt. 9 about one or more pharmaceutically acceptable excipients and/or active substances, provided that the sum of the amounts of the ingredients does not exceed 100 wt. 95. 14. A tablet according to any of the previous items, which is characterized by the fact that it additionally includes one or more pharmaceutically acceptable excipients or additives, or one or more therapeutically, prophylactically and/or diagnostically active substances. 15. A tablet according to any of the previous items, which is characterized by the fact that it additionally includes vitamins or minerals, for example vitamin I) or vitamin K, or magnesium. 16. A tablet according to any of the previous items, characterized in that the tablet is coated with a film coating, for example hydrophobic or hydrophilic polymers, such as, for example, hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPO). 17. The tablet according to claim 16, which is characterized by the fact that the coating is applied in an amount that corresponds to an increase in the weight of the tablet by at most 2 wt. about, for example, at most by 1.5 wt. oh, at most by 1 wt. about or in the interval from 0.25 90 to 0.75 wt. because, based on the mass of uncoated tablets. 18. A tablet according to any of the previous items, which is characterized by the fact that it is in the form of a tablet for chewing, sucking and swallowing. 19. A tablet according to claim 1, which differs in that the tablets have a height of 6 mm to 7.5 mm and a mass of less than 1750 mg with an elemental calcium content of 500 mg. 20. A tablet according to any of the previous items, which is characterized in that it additionally includes a sweetening agent selected from the group consisting of dextrose, fructose, glycerol, glucose, isomalt, lactite, lactose, maltitol, maltose, mannitol, sorbitol, sucrose, tagatose, trehalose, xylitol, alitham, aspartame, acesulfame potassium, cyclamic acid, cyclamate salts (for example, calcium cyclamate, sodium cyclamate), neohesperedin diprochalcone, neohesperedin hydrochloride, saccharin, saccharin salts (for example, ammonium saccharinate, calcium saccharinate, potassium saccharinate, sodium saccharinate), sucralose and mixtures of these components.